The effect of chronic ethanol consumption on hepatocellular functions such as gluconeogenesis will be determined. The influence of the acute effects produced by the oxidation of ethanol on the persistent changes produced by the chronic administration of ethanol will be studied to determine if "insult" is added to "injury" or whether adaptations occur which relieve the effects produced by ethanol oxidation. The role of acetaldehyde in the actions of ethanol will be evaluated by comparing the effects of these agents on several hepatocellular functions e.g., gluconeogenesis. To determine if the effects of acetaldehyde are direct, or due to the metabolism of acetaldehyde, studies will be carried out with inhibitors of aldehyde dehydrogenase e.g., pargyline, disulfiram or cyanamide and with artificial electron acceptors, e.g., methylene blue. The regulation of acetaldehyde metabolism in isolated liver cells or mitochondria will be investigated. The possibility that hepatocellular functions may be more sensitive to acetaldehyde after chronic ethanol consumption will be studied. Factors which contribute to the metabolic adaptation found after chronic ethanol consumption will be further investigated, especially with regard to the role that hydroxyl radicals may play in the oxidation of primary aliphatic alcohols by hepatic microsomes. Evidence for the production of hydroxyl radical during microsomal electron transfer will be presented. An attempt to dissociate the overall pathway of microsomal alcohol oxidation from that of a microsomal drug metabolism will be made. These studies may provide information contributing to the mechanism of pathogenesis of ethanol-induced liver injury, evaluate the role of acetaldehyde in the actions of ethanol, and provide a mechanism for the microsomal alcohol oxidizing system at the molecular level.